Pharmaceutical composition having analgesic and antiphlogistic activities

ABSTRACT

1-(M-TRIFLUOROMETHYLPHENYL)-3-HYDROXY-1H-INDAZOLE OF THE FORMULA:   1-(3-CF3-PHENYL),3-HO-1H-INDAZOLE   AS WELL AS PHARMACEUTICAL COMPOSITIONS CONTAINING IT AS THE ACTIVE INGREDIENT HAVE BEEN FOUND TO HAVE ANALGESIC AND ANTIPHLOGISTIC ACTIVIES.

United States Patent US. Cl. 424-273 Claims ABSTRACT OF THE DISCLOSURE 1- m-trifluoromethylphenyl) -3-hydroxylH-indazole of the formula:

as well as pharmaceutical compositions containing it as 25 the active ingredient have been found to have analgesic and antiphlogistic activities This invention relates to a pharmaceutical composition having analgesic and antiphlogistic activities, which con- 3,781,439 Patented Dec. 25, 1973 3-hydroxy-indazoles having similar structures are of no importance in this respect.

The therapeutical characteristics of ITF 614 can be stressed by the following tests, wherein Wistar-strain rats of both sexes having corporeal weights of from 160 to 190 g. and CF1-strain male mice having corporeal weights of from 19 to 22 g. were used.

The tested products were always administered orally, through a gastric probe, the products being finally suspended in a 0.25% aqueous solution of Methocel 65/400 DG.

The ED and LD as well as the related reliance limits were determined in accordance with the method of Litchfield and Wilcoxon, J. Pharm. Exp. Therap., 96 (1949).

(1) INHIBITION OF THE DEVELOPMENT OF THE CARRAGEEN'IN-INDUCED OEDEMA IN THE RAT.

Female rats having corporeal weights of 160 to 180 g. were used. These animals were kept fasting for 18 hours before the beginning of the tests.

The substances were administered 60 min. before the injection of 0.1 ml. of a 1% aqueous solution of carrageenin in the plantar zone of the rear right paw. 'Im mediately after said carrageenin injection, 4 ml. water were administered orally to each of the rats.

The volume of the paw was determined just after the carrageenin injection and 2, 3 and 4 hours thereafter, by using a diiferential volume gauge. The volume increase of the oedema-affected paw was determined in the pretreated rats in comparison with that of the control rats.

TABLE I.-INHIBITION OF THE DEVELOPMENT CARRAGEENIN-INDUCED OEDEMA IN THE Approxi- Volume increase of the paw in m1. mate equi- Dose plus SE Percent active mg./kg. Number inhibition doses, Products per os of animals 120 min. 180 min. 240 min. (maximum) rug/kg.

Control 10 1.2010. 00 1.321005 1.291010 ITF 614 10 10 1.171008 1.271008 1. 2710. 06 3.7 20 10 1.051007 1. 2010.00 1. 211009 12.5 10 07110.04 1.081010 1.101009 40.8 80 10 05410.03 08110.10 09110.10 55.0

Control A 3 10 0.991000 1.321010 1.341000 Fluophenamic acid- 20 10 07310.07 0.2510. 05 0.991004. 35.5 40 10 05610.04 0.031005 0.7710. 06 52.3 80 10 03310.03 04010.05 0.65:l:0.07 65.0

Control 5 5 10 1.121005 1. 2210.08 1.341008 Benzidamine hydrochloride 20 10 1.021003 1.111005 1. 2610.05 9.0 40 10 07810.09 0.911010 1.101000 30.3 80 10 0.5910. 03 0.8010. 05 1.021007 47.3

1 SE=standard error. tains as the active ingredient 1-(m-trifluoromethylphenyl)- From the data of Table I, the striking inhibiting ac- S-hydroxy-lH-indazole of the formula tion of ITF 614 on the carrageenin-induced oedema can clearly be seen. Said action can be compared with that C0H of fiuophenamic acid and of benzidamine.

(2) INHIBITION OF THE DEVELOPMENT OF GRANULOMATOUS TISSUE IN THE INTEGRAL AND SUPRARENALECTOMIZED RAT This test was eifected in accordance with the method described by R. Mayer et al. in Experientia 6, 469 (1950). Male, Wistar-strain rats having corporeal weights of l-(m trifluoromethylphenyl)-3-hydroxy-1H-indazole, from 1 60 to 180 g. were used. which will be referred to hereinafter, for the sake of The tests were carried out on the above rats by subbrevity, as ITF 614 can be made, for instance, by recutaneously implanting in the right and left scapular zones ducing N nitroso-N-(m-trifluoromethylphenyl)-anthraa pair of sterile, compressed cotton pellets which had nilic acid with zinc and acetic acid as described in Bolbeen obtained by slicing discs from dental rolls. Each lettino di Chimica Farmaceutica, 107, p. 603 (1968).

ITF 614, although already known as intermediate for preparing dialkylaminoalkoxy-indazoles having pharmacological properties, had never been considered previously as to the biological point of view. The fact that said compound shows very interesting antiphlogistic and analgesic properties is surprising, since it is known that the of the pellets had a weight of from 19 to 21 mg. and had been sterilized for 1 hour at C.

In order to ascertain whether an antiphlogistic effect has to be ascribed or not to a suprarenal stimulation, suprarenalectomized rats have also been used for implanting the cotton pellets, which rats were fed with a hypersodic diet.

In each case the products were administered daily for a total of six days and the animals were killed 24 hours after the last administration.

The granulomatous tissue Which formed around the cotton pellets was withdrawn, dried at 70 C. for 12 hours and weighed; of course, the weight of the cotton was considered and subtracted from the weight of the tissue.

The control animals were always fed with distilled water only.

according to Which a 0.5% solutionof acetic acid is injected i.p. in the amount of mL/kg. The analgesic activity was determined on the basis'of the riiifiibf5f the induced writhings.

The capillary permeability Was evaluated on the basis of the amount of Evans Blue, which was administered iv. (5 mL/kg. in a 2% solution) five minutes before the injection of acetic acid. The dye Was colorimetrically titrated in the peritoneal liquor fifteen minutes after the injection of the phlogosis-inducing agent.

TABLE II.INHIBITION OF THE DEVELOPMENT OF GRANULOMATOUS TISSUE INDUCED BY IMPLANTING COTTON PELLETS IN INTEGRAL RATS Weight (mg.)

Dose, Number of the granumg./kg./day of lomatous Percent Products per 05 animals tissueiSE inhibition Control 12 69. :3. 04 IIF 614 10 1O 49. 55:2. 81 16. 2 10 46. :2. 48 21. 8 10 44. 05:3. 02 25. 5 8O 20 48. 712. 27 34. 4

Control H A 12 59. 15:3. 04 Fluophenamic acid 10 1O 49. 9i4. 86 15. 5 20 10 47. 55:2. 64 19. 6 40 20 43. 55:3. 44 26. 3

Control r 12 67. 05:3. 62 Benzidamine hydrochloride 20 10 63. 0i4. 68 5. 9 4O 10 52. 8i3. 91 21. l. 80 1O 47. :1. 41 29. 1

RENALECTOMIZED RATS Weight (mg) Dose, Number of the granumg. lkgJday o lomatous Percent Products per os animals tissueiSE inhibition Control 10 66. 45:2. 38 ITF 614 10 1O 59. 45:2. 46 10. 5 2O 10 56. 05:2. 84 15. 6 40 10 52. 6&2. 63 20. 7

Cnntml 10 56. 45:2. 81 Fluophenamic acid 10 10 52. 45:3. 12 7. 0 20 10 45. 85:2. 42 18. 8 40 10 44. 25:2. 26 21. 6

Contro1- I0 40- 1:1:3. 25 Benzidamine hydrochloride 20 1O 54. 35:2. 84 9. 6 40 10 48. 95:2. 66 18. 6 80 10 41. 05:1. 80 31. 4

From the data of Tables II and III, the inhibiting action of ITF 614 on the development of granulomatous tissue can clearly be seen.

The products to be tested were administered thirty minutes before the injection of acetic acid.

TABLE IV.-ANALGESIC ACTIVITY AND EFFECT ON THE PERITONEAL CAPILLARY PERMEABILITY THE MOUSE Dose, Numberot Percent Mg. Evans Percent;

Writhings, Permeabil- Number of Ing./kg. Writhings inhibi- Blue per inhibi- EDm (0.11.), ity, approx. Produ ts animals per os 5:SE tion mouseiSE tion mg./kg. D -l s- Control 10 32. 85:4. 24 42. 85:3. 15 10 10 17. 014. 52 48. 0 36. 05:5. 22 15. 9 60 ITF 614 10 20 10. 55:3. 02 67. 6 34. 25:3. 58 20. 1 9. 2 (3. 28-25. 76)

1O 40 8. (iii 40 73. 9 26. 35:4. 07 38. 5 Control 10 44. 25:2. 49 37. 45:5. 96

10 10 32. 75:6. 10 26. O 38. 15:4. 70 0 Fluophenamie acid 10 0 26. 1&3. 28 41. 0 34. 75:4. 34 7. 2 28 (12. 7-61. 6)

10 40 18. 35:3. 19 58. 5 25. 6:b6. 08 31. 6 Control 10 37. 3i? ()6 54. 2i4. 15

10 20 23. 9&3. 45 35. 9 43. 35:5. 77 20. 1 Benzidamine hydrocl1l01ide 10 40 15. 45:6. 34 58. 7 36. 95:6. 31 31. 9 30. 5 (17. 4-53. 37) 70 (3) ANALGESIC ACTIVITY AND EFFECT ON THE 'PERITONEAL CAPILLARY PERMEABILITY IN THE MOUSE From the data of Table IV, the higher activity of ITF 614 with respect to those of fiuophenamic acid and of benzidamine can be seen.

(4) ANALGESIC ACTION IN THE RAT In these tests, male rats having corporeal weights of from to g. were used, which had been kept fasting for 18 hours but fed with water at will.

The analgesic action was quantitatively determined in accordance With the method described by Randall and Selitto, Arch. Int. Pharmacodyn., 111, 409- (1957). In

this procedure, the analgesic activity was measuredon the basis of the increase of the algogenic threshold, which latter was determined by applying a uniformly increasing pressure on the rear plantar zone in which an oedema had been previously induced by a topical injection of 0.1 ml. of a 20% brewers yeast suspension in distilled water.

In order to better define the kind of the analgesic action, particularly in order to determine whether said action can be related to an antiphlogistic action, the algogenic threshold was determined, at the same time, on the normal, contralateral paw.

The algogenic threshold determinations were efiected thirty minutes before administering the products and 60, 120 and 180 minutes thereafter. The brewers yeast suspension had been injected into the plantar zone of the paw sixty minutes before the first determination of the algogenic threshold.

TABLE V Analgesic action in the rat-normal paw (5) EFFECTS ON THE BEHAVIOR OF THE MOUSE In these tests male CF-l mice were used, which had a weight of from 19 to 21 g. and had been kept fasting .for 18 hours.

The products to be tested were administered orally in various doses to groups of five mice per each dose level.

Doses of 10, 30, 60, 100, 300, 600 and 1000 mg./kg. were used.

The modification of the behavior of the tested animals was observed in accordance with the method of Irwin, Gordon Res. Conf. Med. Chem.New London, NH, 3/ 7-8, p. 133 (1959) during the first 4 hours after the administration of the products and, thereafter, daily for 5 days. The immediate mortality rate and that which occurred during the five days after the treatment were also determined.

Algogenic threshold in arbitrary unitsiSE Time in min. from the treatment Dose, at Maximum mgJkg. Number of min. increase, Products per os animals before 60 min. 120 min. 180 min. percent ITF 614 10 10 14. 7i1. 33 14. 65:1. 19 14. 75:0. 90 14. 55:0. 74 0 20 20 12. 7il. 04 13. 4i1. 44 12. 7i1. 10 14. 1i1. 34 16. 5 20 12. 455:0. 68 14. 95:1. 09 14. 2i0. 87 14. 3i0. 86 20. 2 80 10 12. 9i1. 16 12. 95:0. 92 13. :1. 43 12. 4i1. 25 3. 8

Fluophenamic acid .1....'.:...'..;..' 10 10 18. 45:1. 57 20. 5i1. 22 15. 6i1. 46 17. 05:1. 29 11. 4 20 10 19. Oil. 17 18. 95:1. 46 19. 4i1. 54 18. 7i1. 61 2. 1 40 10 15. 2i1. 15. 2i1. 24 17. 25:0. 14. fiil. 35 13. 0

Benzidamine hydrochloride.; 20 10 9. :0. 85 9. 95:0. 89 10. 45:0. 94 10. 25:1. 02 7. 2 40 10 10. 9i1. 13 11. 65:0. 98 12. 1i1. 34 11. 9i1. 15 11. 1 8O 10 13. 2il. 40 13. 6i0. 90 14. 15:0. 77 14. 3i0. 59 8. 3

TABLE VI Analgesic action in the rat-oedema-afiected paw Algogenic threshold in arbitrary unitsiSE Time in min. from the Dose, treatment at Maximum mg./kg. Number of 30 min. increase, ED50, Products per 05 animals before 60 min 120 min. 180 min. percent mgJkg.

ITF 614 10 10 8. 2i0. 33 10. 3i0. 80 10. Gil. 03 9. 0i0. 98 20 20 6. :0. 65 9. 2i1. 14 8. 45i0. 86 10. 6i0. 90 40 2 0 6. i0. 46 9. 75i0. 91 11. 15i1. 46 12. 6i0. 76 80 10 8. 1i0. 78 11. 75:1. 16 16. 05:1. 04 12. 8i2. 13

h n cid- 10 10 10. 95:1. 72 11. 55:1. 92 12. 25:1. 57 12. 8i1. 62 Fluop 9 me a 20 10 10. 4i0. 73 14. 9i1. 90 15. 5i1. 68 15. 4i1. 79 40 10 8. 85:1. 20 14. 85:2. 54 16. 85:1. 18 13. 15:0. 82

1 nc h dr0ch1orlde 20 10 7. 65:1. 24 8. 65:1. 07 8. 5i0. 94 7. 85:0. 69 13. 1 Benz dam! y 40 10 8. 5i0. 71 9. 35:0. 35 10. 45:0. 80 11. 2i1. 21 31. 7 56 80 10 6. 9i1. 10 9. 85:0. 94 11. Gil. 09 11. 4i1. 23 68. 1

From the data of Tables V and VI, a particularly strik ing analgesic action of ITF 614 can be seen.

The animals, fed with food or water at will, were kept in an environment thermostated at 21-22 C.

TABLE VIL-EFFECTS ON THE BEHAVIOR OF THE MOUSE Mortality rate Dose, mgJkg. Spent. Resp. Convul- Straight Muscu- Resp. Palp. Imme- De- Products per os activ. Passiv. to ache Tremor sion Ataxia refi. lar tone rate opening diate layed 300 -1 +2 --2 0 0 0 3 -1 0 1 0/5 0/5 600 2 +3 2 0 0 0 -3 2 --2 -2 0/5 2/5 1, 000 3 +4 2 0 +1 0 4 3 2 -3 0/5 5/5 Fluophenamic acid. 1 +1 -1 0 0 0 -2 --1 0 0 0/5 0/5 300 --3 +2 2 0 0 0 -3 -1 -2 0 1/5 0/5 600 3 +4 4 +1 0 +3 4 -2 3 0 1/5 1/5 1, 000 -4 +4 4 +1 0 +3 --4 3 -3 0 4/5 0/5 Benzidamine hydro- 30 0 0 1 0 0 0 2 0 0 0 0/5 0/5 hloride 60 0 +1 2 0 0 0 3 0 0 0 0/5 0/5 100 1 +1 3 +1 0 +1 -3 -1 0 0 0/5 0/5 300 4 +3 -3 +2 +4 +3 -3 0 0 1/5 0/5 600 +2 +4 +4 -4 0 0 3/5 0/5 1, 000 0 0 5/5 0/5 ode:

1=slight decrease. 2=moderate decrease. -3=la.rge decrease. --4=extreme decrease. +1=s1ight increase. +2 =mo derate increase. +3 =large increase. +4=very large increase. 0=no noticeable efiects.

In addition to the above experiments which refer to acute tests, further tests were carried out to determine the chronic characteristics of the drug in question.

Thus, a test was carried out on the oedema induced by injecting carrageenin in the plantar zone of the rear paw of rats, as described by Winter et al., Proc. Soc. Exp. which had been injected with only the carrier used for Biol., 111, 544, New York (1962). preparing the mycobacteria suspension.

Furthermore, the effect of the drug was evaluated on The products to be tested were administered orally the arthritis produced by injecting Freunds adjuvant in through a gastric probe, in the form of a suspension in accordance with the method described by Stoerk et a1., 1 a 0.25% 65/4000 DG Methocel solution. in Am. J. Path, 30, 616 (1954) and then modified by Pear- The arthritic syndrome was induced by intraplantarily son [Proc. Soc. Exp. Biol, 91, 95 (1956) and Arthr. and injecting the animals with 0.1 ml. of a fine suspension of Rheum, 4, 440 (1959)]. killed and dried mixed PN, DT and C strains of the To complete the pattern of analogies with the rheumahuman Mycobaczerium tuberculosis. Said suspension was toid arthritis in human beings, the modification of the prepared in paraifin oil at the concentration of 5 mg./ erythrosedimentation rate which ha been found after a volumes of the injected paw and of the contralateral paw, Freunds adjuvant injection [BolL Soc. Ital. Biol. Sper., The treatments with the substances to be tested started 45, 36 (1969)] should be considered in addition. the day before the injection of the Freunds adjuvant and While a measure of the volume of the paw both before were continued throughout the test period (to a total of an after the carrageenin injection is sufficient .for evalu- 31 days) at a rate of 6 administrations per week. The ating the development of the carrageenin-induced oedema, volumes of the injected paw and of the contralateral paw, which is localized in the paw wherein the injection has the functionality of the four paws, the intensity of the been effected, suitable parameters must be chosen in orsyndrome (recorded in an arbitrary scale) and the der to permit that the most reliable evaluation of the corporeal weight were measured the day before the incomplex syndrome induced by injecting the Freunds adjection of the Freunds adjuvant, the next day and the juvant is carried out, which parameters should also be third day after the said injection,.then,.for the remaining compatible with a reasonable time and energy expense. test period, twice a week, that is on Tuesday and on Any variations of said parameters should be quantita- Friday. tively measurable so that a statistic evaluation can be The erythrosedimentation rate was determined on blood effected, if desired, samples drawn from the tail after 14 and 31 days of the The following parameters have been measured: the treatment. volume of the leg injected with a mycobacteria emulsion; The volumes of the right and left paws were measured the volume of the contralateral leg; the functionality of With the Differential Volume Gauge produced by the firm the four legs; the syndrome intensity as expressed in an Basile (Milan, Italy). arbitrary, although well coded scale; and the erythrose- The paw functionality was determined by placing the di m ti t rats, one at a time, on a vertically disposed net having As a further complementary parameter, the increase 3 X 3 meshes and recording the number of thc P of the animal corporeal weight has been measured, in used y each animal to hold on to the net y corrctly order to prevent overdosages of the substances and to moving the toes normal animals, this Value is four; exclude the possibility that the observed effects could be for animals which badly move their Paws, this Value anyhow ib to a possible toxic action goes down to reach zero when the animal badly moves all the four paws. MATERIALS AND METHOD The seriousness of the syndrome was expressed in (a) Cal-rageeniminduced oedema in the rat values frtom zero to four representing a global, subjective Female rats having corporeal weights of from 150 to Ju fl gi was as follows: 170 g., which had been kept fasting for 18 hours, were used.

The products to be tested were administered orally 1 hour before the intraplantar injection of 0.1 ml. of a 2 i {except that on the Injected leg; 1% carraggenin aqueous Solution. 2-? lg ll swellll mg offttlllie contralateral leg also The plethismographic determination of the paw volume fi g 0 e lcontrrilateral leg also was effected immediately after, and 1, 2, 3 and 4 hours g egs a after the injection of the phlogogenic agent. The volswelmg 3 th e on: legs the tall Sometimes the ume increase of the paw in the control rats was compared mm e an e ears with that of the treated rats.

The dose effective for inhibiting 50% of the oedema occurrence was determined graphically. The determination of the erythrosedimentation rate At least three dose levels were investigated for each was efifictd on Small blood Samples y using Wintrobe product and at least ten rats were used for each dose capillary iubfis, the b10061 coagulation haying Been P l L veilted by the addition of Choay heparin (0.04 ml. heparin so ution at a concentration of 5000 i.u./rnl. added to 0.20

(b) Arthritis induced by Freund S adjuvant the rat ml. blood); the rate was expressed in mm./ minutes.

The tests were performed on female Wistar-strain The results of the above described tests were sumrats having an initial weight of from to g. 65 marized in the following tables.

TABLE VIII Each group of animals which was treated with the substances to be tested comprised 8 rats; in addition, a further group of 8 untreated rats was used, which rats had been injected with the Freunds adjuvant; and one more group of untreated animals was used, i.e. animals Freunds adjuvant-injected paw. Average volume increase in ml.=l=SE. Data of each test grouped D/lpse, Days from the starting of the administrations mg. g.,

Products as 3 5 8 11 14 17 21 24 28 31 Fluo henamic acid 10 1.006 1. 012 1. 044 0. 912 1. 1. 412 1.537 1. 462 1.581 1. 337 $0. 072 10. (J65 :l=0. 087 =|=O. 093 it). 091 5:0. 134 =l=0. 142 =l=0. 171 510.242 =l:0. 203

IT]? 614 10 0.931 1. 118 1. 106 1. 187 1. 606 1. 931 2. 237 2. 225 2. 306 2. 293 5:0. 086 5:0. 169 :l=0. 127 5:11.097 =|=0. 127 $0. 192 it). 206 =|:0. 218 i0. 222 it). 231

Control, adjuvant 1. 068 1. 593 1. 568 1. 331 1. 718 2. 118 2.631 2. 568 2. 462 2. 300 =!:0. 077 ill. 210 :!:0. 260 :bO. 173 $0. 215 $0. 262 =l=0. 273 :!=0. 254 $0. 298 =l=0. 322

TAB LE X Functionality of the legs-average valuesiSE (legs used to hold to the vertically disposed net) I/)1ose, Days from the starting of the administiatibfis 7 9 mg. g.

Products 's 3 s 11 14 17 21 24 2s 31 Fluophenamic acid 3. 250 3. 375 3. 250 3. 625 3. 125 2. 750 2. 875 0. 750 2. 625 2. 625 $0. 163 i0. 182 5:0. 163 $0. 182 5:0. 226 i0. 163 0. 226 5:0. 249 5:0. 182 5:0. 182

ITF 614 10 3. 625 3. 625 3. 375 3. 375 2. 025 2. 500 2. 250 2. 125 2. 000 2. 125 5:0. 182 i0. 182 5:0. 182 5:0. 263 5:0. 263 5:0. 373 5:0. 366 5:0. 350 i0. 377 5:0. 295

Control, adjuvant 3. 125 3. 125 3. 125 2. 750 2. 500 2. 125 2. 000 1. 750 1. 750 2. 000 5:0. 125 5:0. 125 5:0. 125 5:0. 249 5:0. 422 5:0. 350 i0. 327 5:0. 313 5:0. 412 5:0. 327

Control, parafiin Oil 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000 $0. 000 5:0; 000

ITF 614 2O 3. 125 3. 000 3. 375 3. 375 3. 250 2. 625 2. 000 2. 125 2. 250 2. 375 5:0. 125 5:0. 000 i0. 182 5:0. 182 5:0. 163 if). 182 $0. 267 5:0. 226 $0. 249 :EO. 263

ITF 614 40 3. 125 3. 000 3. 250 3. 375 Z. 875 2. 750 2. 375 2. 375 2. 375 2. 375 $0. 125 5:0. 000 5:0. 163 5:0. 182 5:0. 125 5:0. 163 5:0. 183 5:0. 183 5:0. 183 5:0. 183

Control, adjuvant 3. 125 3. 000 3. 125 3.250 2. 500 2. 125 1. 875 1. 625 1. 875 1. S75 10. 125 5:0. 000 5:0. 125 $0. 163 i0. 422 $0. 350 5:0. 295 5:0. 323 5:0. 350 5:0. 398

Control, paraifin Oil 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 5:0. 000 5:0. 000 5:0. 000 i0. 000 :bO. 000 5:0. 000 5:0. 000 5:0. 000 $0. 000 5:0. 000

Fluophenamic acid 20 3. 500 3. 625 3. 750 3. 875 3. 875 3. 125 2. 750 2. 625 2. 750 2. 500 5:0. 189 5:0. 182 5:0. 163 5:0. 125 5:0. 125 5:0. 226 5:0. 193 5:0. 182 $0. 313 5:0. 189

Control, adj uvant 3. 250 3. 250 3. 625 3. 750 3. 375 1. 875 1. 375 1. 375 1. 250 1. 250 5:0. 163 5:0. 163 5:0. 182 5:0. 163 5:0. 324 i0. 515 5:0. 420 5:0. 460 5:0. 453 5:0. 453

Control, paraflln oil 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000 10. 000 i0. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000

lllIephenamic acid 40 3. 250 3. 375 3. 500 3. 625 3. 125 3. 750 2. 500 2. 500 2. 125 1. 750 5:0. 163 5:0. 182 5:0. 189 5:0. 182 :L0. 226 $0. 410 5:0. 378 5:0. 378 5:0. 398 10. 313

Control, adjuvant 3. 125 3. 125 3. 625 3. 625 3. 000 2. 875 2. 000 1. 875 1. 250 1. 250 :0. 125 5:0. 125 5:0. 182 $0. 182 $0. 189 5:0. 226 5:0. 378 5:0. 350 5:0. 412 5:0. 313

Control, paraffin oil 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 4. 000 $0. 000 $0. 000 5:0. 000 $0. 000 5:0. 000 5:0. 000 5-. O. 000 5:0. 000 5:0. 000 5:0. 000

TABLE XI Intensity of the syndrome-average values i SE IIJKOgSB, Days from the starting of the administrations mg.

Products 0% a 5 s 11 11 17 21 24 2s 31 Fluophenamic acid 10 0. 000 0. 000 0. 000 0. 125 0. 250 0. 625 1. 000 1. 250 1. 125 1. 125 5:0. 000 5:0. 000 5:0. 000 5:0. 124 5:0. 163 i0. 32-3 5:0. 377 $0453 5:0. 350 i0. 398

ITF 614 10 0. 000 0. 000 0. 250 0. 500 0. 750 1. 125 2. 000 2. 125 2. 125 2. 125 i0. 000 5:0. 000 5:0. 163 5:0. 267 5:0. 412 5:0. 479 5:0. 463 $0. 549 i0. 475 $0. 549

Control, adjuvant.. 0. 000 0. 000 O. 125 0. 875 1. 375 1. 750 2. 000 2. 250 2. 375 2. 500 5:0. 000 5:0. 000 5:0. 124 5:0. 350 5:0. 497 5:0. 559 i0. 499 5:0. 559 $0. 595 5:0. 534

Control, paratfin oi1 .4. 0. 060 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 O. 000 0. 000 5:0. 000 5:0. 000 i0. 000 5:0. 000 i0. 000 5:0. 000 i0. 000 5:0. 000 5:0. 000 5:0. 000

ITF 614 20 0. 000 0. 000 O. 000 0. 000 0. 750 1. 750 2. 375 2. 000 2. 500 1. 875 5:0. 000 5:0. 000 5:0. 000 5:0. 000 $0. 313 5:0. 491 5:0. 497 $0. 422 5:0. 499 5:0. 479

ITF 614"" 40 0. 000 0. 000 0. 000 0. 000 0. 750 0. 875 1. 750 2. 125 2. 375 2. 000 5:0. 000 $0. 000 5:0. 000 :h-O. 000 5:0.313 5:0. 479 $0. 412 5:0. 125 :hO. 323 5:0. 267

Control, adjuvant 0. 000 0. 000 0. 000 0. 500 1. 000 1. 750 2. 750 2. 625 2. 875 2. 875 5:0. 000 5:0. 000 5:0. 000 5:0. 189 5:0. 490 5:0. 491 5:0. 497 5:0. 491 $0. 398 5:0. 350

Control, paraffin oil 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000 i0. 000 5:0. 000 5:0. 000 5:0. 000 i0. 000

Fluophenamic acid- 20 0. 000 0. 000 0. C00 0. 000 0. 375 1. 250 1 250 1. 875 1. 875 -2. 000 5:0. 000 $0. 000 i0. 000 5:0. 000 i0. 263 5:0. 453 5:0. 453 5:0. 580 5:0. 580 5:0. 534

Control, adjuvant. 0. 000 D. 000 O. 000 0. 000 1. 125 2. 000 2. 625 2. 875 2. 875 2. 875 5:0. 000 5:0. 000 5:0. 000 i0. 000 5:0. 479 5:0. 534 5:0. 460 5:0. 295 i0. 295 i0. 226

Control, paraffin 011... 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 5:0. 090 $0. 000 5:0. 000 5:0. 000 5:0. 000 $0. 000 5:0. 000 5:0. 000 5:0. 000 5:0. 000

Mephenamic acid 40 0. 000 0. 000 0. 000 0. 000 0. 875 1. 125 1. 500 1. S 2. 125 2. 375 5:0. 000 5:0. 000 i0. 000 5:0. 000 i0. 580 5:0. 639 i0. 567 5:0. 580 5:0. 515 i0. 460

Control, adjuvant 0. 000 0. 000 0. 000 0. 125 0. 500 1. 000 1. 625 2. 500 2. 875 3. 250 5:0. 000 $0. 000 5:0. 000 5:0. 124 5:0. 267 5:0. 378 5:0. 532 5:0. 534 5:0. 350 5:0. 313

Control, parafiin oil 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000 0. 000

TABLE XII .ERYTEIROSEDIMENT'ATION RATE.

AVERAGE: VALUES Days from the starting of the Dose, administrations mg.."kg., 9 Products 14 31 Fluophenamic acid 4. 500i0. 364 3587.5:30. 588 ITF 614 10 5.625;i:1. 723 0. 625:1:1. 703 Control, adjuvant. 6. 750:31. 457 8. 375i1. 444 Control, paraffin oil 1. 66610. 4777 2. 00010. 488

ITF 614 5. 312:1:0. 801 5. 875=|=0. 929 10 ITF 614 4. 312:1;0. 908 3. 000=|:0. 526 Control, adjuvant 4. 9:37:30. 512 7. 375=l=1. 368 Control, paraifin oil 2. 250=|=0. 602 1. 916=l=0. 416 Fluophenamic acid 6. 062:32. 755 3. 437i0. 394 D0 3. 2:30:30. 796 2. 437=l;0. 512 Control, ad uv 8. 437=|=2. 051 14. 250=|=4. 250

Control, parafiin o 2. 083=|=0. 436 2. 916i0. 436 Mephenamic acid 2. 625i0. 479 5. 00010. 597 Do 2. 437=|=0. 764 4. 437:30. 671 Control, adjuvant- 4. 31211. 105 10. 062:1;1. 643 Control, paraflin o 2. 166:30. 601 1. 916=30. 374

TABLE XIII Average corporeal weight increase in g.iSE. Data of each test grouped D/fise, Days from the starting of the administrations mg. g., Products 03 3 5 3 11 14 17 21 24 23 31 Fluophenamjc acid 10 1.375 0. 625 3. 125 11.375 11.375 11.375 15. 625 10.625 15. 623 21.375 =31. 315 =31. 751 =32. 662 $2. 433 =30. 365 =34. 425 =35. 126 =35. 545 =34. 765 $3. 333

ITF 14 10 2. 500 1.375 3.750 9.375 11.250 3.750 3. 750 2. 500 4.375 10.625 =31. 636 =31. 315 =31. 250 =32. 203 =31. 570 =32. 930 =37. 113 =39. 496 =39. 339 =310. 103 n -m1, adjuvant 3. 125 1. 250 6. 375 4.375 4.375 3.750 2. 125 3. 125 11.250 12. 500 =31. 375 =32. 059 =33. 393 :!:4. 475 =35. 213 =35. 324 =35. 340 =34. 323 =34. 605 =34. 432

r paraffin 011 7.500 12.500 23. 333 31. 666 33.333 40.333 46. 666 50. 000 54. 166 55.333 =32. 313 =33. 095 $3. 333 =35. 725 =35. 426 =35. 688 =36. 412 =35. 773 =34. 362 =34. 549

ITF 6. 250 7.500 12.500 17.500 10.625 5.000 1.250 1. 250 1.875 3.750 =31. 250 =31. 339 =31. 336 =31. 636 5:1. 990 =33. 535 =34. 199 =33. 503 =34. 994 =34. 605

ITF 614 5.625 7. 500 9.375 16.250 11.250 11.375 5. 000 2. 500 8.125 16. 000 i1. 752 =|=1. 636 $2. 903 =33. 629 =35. 649 =36. 375 =35. 324 =35. 033 =35. 504 =36. 196

001mm, djuvgmt 6. 250 6. 675 6. 256 11. 000 9. 373 9. 375 1. 375 3. 750 1. 375 1. 250 =30. 313 =30. 915 =31. 567 =32. 672 =33. 195 :33. 463 =32. 662 =33. 1167 i3. 033 =34. 605 Control, m n 9. 166 10.333 13. 333 17.500 25.000 23.333 33.333 34. 166 37.500 33. 333 =31. 536 i0. 313 =32. 163 =32. 315 =32. 532 =33. 073 =33. 333 =33. 745 =34. 609 =34. 772

d 20 2.500 4.375 15.000 25.625 33.125 33.125 20.000 29. 250 39. 750 35, 000 Fluophenamlc am =30. 945 =30. 625 $1. 339 =33.195 =32. 439 =32. 302 =36. 614 =36. 301 :6. 533 =36. 473

111; 1. 250 0. 500 9.375 23.000 30.250 13.000 17.375 14.000 17.750 13. 375 adluva i2. 943 12. 145 =33. 744 =31. 77o =32. 943 =35. 130 $3. 451 =35. 901 =36. 390 =36. 643

611 13 3. 330 2. 500 16. 330 21.000 41.330 43.500 61. 330 67. 670 66. 500 65, 600 Cmmol para =31. 666 =36. 354 =31. 533 =32. 379 =34. 733 =34. 616 =34. 366 =34 767 =34. 956 =34. 726

40 4.375 0.625 13.125 20.000 16.375 13.750 13.725 21. 375 25. 000 2 375 Flmphemmm field =32. 203 =32. 203 =33. 265 =33. 273 =33. 070 =39. 624 =310. 561 =310. 729 =311. 340 =310. 915

- 1. 250 1.375 10. 000 13. 750 13. 125 20. 000 11.250 7.500 6, 375 Comm adjuvant 41. 250 =32. 099 =31. 543 $1. 567 =33. 333 =34. 724 =36. 250 i6. 333 =35. 731 =36. 461

The global activity indexes are shown in the following Table XV.

TABLE xv Global activity indexes Volume oi Percent inhibition on- Dose, The The Erythromg./kg., injected contralateral Leg func- Syndrome sedimenta- Activity Products 05 paw paw tionality intensity tion rate index Mephenamic acid-.- 40 17.6 31. 3 19.3 16.8 65. 5 150. 5 30 19.3 47. 6 23. 1 33. 9 72. 9 206. 3

Fluophenamic acid 10 41. 7 59. 4 38. 1 58. 5 58. 9 256. 6 20 44. 3 73. 7 51.2 40. 0 74. 5 239. 2 40 55. 5 34. 4 50. 4 47. 3 96. 1 334. 2

17 EXAMPLE 4 200 mg. capsules Product Lactose Starch Talc Magnesium stearate EXAMPLE 5 1% suspension to be used orally Product Hydroxyethylcellulose Sucrose Nipagine Nipasol Water, balance to 100 ml.

EXAMPLE 6 2% suspension to be used orally Product Hydroxyethylcellulose Sucrose Nipagine Nipasol Water, balance to 100 ml.

What is claimed is:

10 in a pharmaceutically acceptable carrier to be adminis- LO tered orally in the form of troche, tablet, pill, syrup, 20 capsule, or rectally in the form of suppository.

01 2. The composition of claim 1 containing 100-200 6 milligrams of active ingredient.

3. A method for relieving pain or alleviating inflammatory syndromes in animals, which comprises administering an analgesic or antiphlogistic eifective amount of the pharmaceutical composition of claim 1 to an animal in need of such treatment.

4. The method of claim 3 wherein the daily dose of active ingredient is from 300-700 milligrams.

5. The method of claim 4 wherein each individual dose 5'? contains from 100-200 milligrams of active ingredient. References Cited 11 Farmaco, May 1970, N0. 5, pp. 386 105. Chemical Abstracts, :77855k (1969).

1. A pharmaceutical composition having analgesic or antiphlogistic activities comprising an analgesic or anti- JEROME D. GOLDBERG, Primary Examiner 

